Currently there is no method available to predict response to farnesyltransferase inhibitors. Tipifarnib was the first farnesyltransferase inhibitor (FTI) to be tested in the clinic. Rowinsky et al. (2006). It has demonstrated significant activity in hematological disorders including AML, MM, MDS and CML, with complete response rates in AML and MDS of up to approximately 15%. Mesa et al. (2006); Karp et al. (2001); Lancet et al. (2007); Fenaux et al. (2007); and Harousseau et al. (2007). FTIs function by competitively inhibiting the addition of a farnesyl moiety to a number of important signaling molecules including Ras. Rowinsky et al. (2006); and Cox et al. (2002).
Some molecules, such as Ras, that are implicated in cancers must be farnesylated by the farnesyl transferase enzyme in order to interact with the inner leaflet of the plasma membrane of the cell and become involved in various signaling pathways. Ras is not the only protein implicated in cancer that has a CAAX box that is prenylated. Farnesyl transferase inhibitors (FTIs) are therapeutic agents that inhibit the covalent attachment of the carbon farnesyl moieties to the C-terminal CAAX motif of various proteins. They have utility in the treatment of cancers and proliferative disorders such as leukemia. Acute myelogenous leukemia (AML) is among the diseases that can most beneficially be addressed with FTIs.
As is true in the case of many treatment regimens, some patients respond to treatment with FTIs and others do not. Prescribing the treatment to a patient who is unlikely to respond to it is not desirable. Thus, it would be useful to know how a patient could be expected to respond to such treatment before a drug is administered so that non-responders would not be unnecessarily treated and so that those with the best chance of benefiting from the drug are properly treated and monitored. Further, of those who respond to treatment, there may be varying degrees of response. Treatment with therapeutics other than FTIs or treatment with therapeutics in addition to FTIs may be beneficial for those patients who would not respond to FTIs or in whom response to FTIs alone is less than desired.
Historically, the mutation status of the ras gene was considered to be a candidate biomarker for patient response to FTIs. This rationale was based on pre-clinical evidence that FTIs could block Ras-transformed cells, and that specific point mutations within ras genes cause constitutive activation of the Ras pathway in many cancers. End et al. (2001) Reuter et al. (2000); and Bos et al. (1989). Since it is generally accepted that tumors are heavily reliant on the activation of one or two pathways (“oncogene addiction” hypothesis), it follows that patients whose tumors are promoted by a particular pathway should respond to drugs that inhibit that pathway. Weinstein et al. (2006). However, pathways can be activated by multiple events and it has been found that Ras can be up-regulated in the absence of activating Ras mutations. Ehmann et al. (2006). Furthermore, no correlation between ras mutations and response to FTIs has been demonstrated in clinical studies. Karp et al. (2001); and 20070048782. Indeed, while several early clinical studies focused on cancers that exhibited high frequencies of ras mutations the response rate was disappointingly low in those trials. Mesa (2006); Rao et al. (2004); and Van Cutwem et al. (2004).